The precise control of leukocyte adhesivity is critical in maintaining effective homeostasis of the immune response, for lymphocyte motility, homing, and recirculation, the localization of leukocytes at sites of inflammation, and antigen presentation. A small subset of integrins, namely α4, β2, and β7 integrins, largely controls leukocyte adhesion, and related functions (1).
The integrins are a superfamily of transmembrane receptors which mediate cell-extracellular matrix and cell-cell interactions. Each integrin consists of noncovalently paired alpha and beta subunits. There are presently 8 beta and 18 alpha subunits known. The β7 subunit partners with two α chains to form two heterodimeric molecules, namely α4β7 and αEβ7.
Integrin adhesivity is regulated by a complex array of intracellular signalling pathways that impinge on integrin subunit cytoplasmic domains, and trigger changes in integrin conformation, clustering (2), affinity for ligands (3, 4), and cell spreading (5), all of which contribute to increased cell adhesion (6-8).
In the case of β7 integrins, it has been demonstrated that small GTP-binding proteins induce integrin α4β7-mediated T cell adhesion to the mucosal addressin MAdCAM-1 in a hierarchical fashion, by a mechanism predominantly involving changes in receptor avidity due to ligand-induced clustering (9). The control of β7-integrin adhesion is critical as the two β7 integrins, α4β7 and αEβ7, play key roles in forming and maintaining gut immunity (10, 11), and α4β7 contributes to leukocyte infiltration into the islets of Langerhans in Type I diabetes (12), and the central nervous system in demyelinating diseases such as multiple sclerosis (13). α4β7 mediates the adherence of lymphocytes to high endothelial venules (HEV) at such chronically inflamed sites via its preferred ligand MAdCAM-1 (14, 15), whereas αEβ7 mediates the adhesion of intraepithelial lymphocytes to the intestinal epithelium by an interaction with E-cadherin (17,18).
Additionally, “inside-out” transmembrane signalling pathways reveal that the short (˜47-66 amino acid residues) integrin β subunit cytoplasmic domains serve as substrates for cellular kinases, and are phosphorylated upon cell activation (19-22). Certain β subunit cytoplasmic domains directly interact with, and share, cytoskeletal elements including talin, α-actinin, paxillin, and filamin. Some share intracellular signalling molecules such as integrin-linked kinase (ILK), and Rack1, yet potentially associate in an exclusive fashion with an array of other intracellular signalling molecules that may ultimately dictate the nature of integrin-specific “inside-out” and “outside-in” signalling pathways. The human WD repeat protein WAIT-1 specifically interacts with the cytoplasmic tails of β7-integrin α and β subunits (β7, α4, and αE), but not those of integrin β1, β2, and αL subunits (23).
Notwithstanding the above knowledge, the nature and identity of the molecules which associate with the integrins and regulate their activity are largely unidentified. Similarly, the regulatory sites or motifs present within the integrin subunits have not been fully characterised. Accordingly, there is still much to be understood of the precise mechanisms which allow for regulation of integrin activity and concomitantly cell-cell or cell-extracellular matrix interactions.
In light of the role integrins play, particularly β7 integrins, in regulating leukocyte activity and targeting, and their implication in the development of certain inflammatory disorders, elucidating the precise mechanisms by which their function may be regulated may allow for control thereof, with concomitant amelioration of relevant inflammatory disorders.
Bibliographic details of the publications referred to herein are collected at the end of the description.
Abbreviations used herein: β7cyt, integrin β7 subunit cytoplasmic domain; CARD, cell adhesion regulatory domain; GST, glutathione S transferase; ICAM-1, intercellular adhesion molecule-1; MAdCAM-1, mucosal addressin cell adhesion molecule-1; PMA, 4β-phorbol 12 myristate 13-acetate; VCAM-1, vascular cell adhesion molecule-1.